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Biomedical subjects

G Faller

Publications and source records attributed to G Faller.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mucosal production of antigastric autoantibodies in Helicobacter pylori gastritis.

BACKGROUND: Apart form bacterial virulence factors of Helicobacter pylori, certain host factors influence the pathogenesis of H. pylori gastritis. In particular, antigastric autoantibodies that are detectable in the sera of a substantial proportion of H. pylori were shown to correlate with the development of gastric atrophy. The aim of this study was to analyze the possible antigastric autoimmune response in H. pylori gastritis at the site where the action is, i.e. , in the gastric mucosa. MATERIAL AND METHODS: Gastric biopsy specimens from antrum and corpus mucosa of 24 H. pylori-infected and of 33 noninfected patients were cultured for 3 days, and tissue culture supernatants were analyzed for the amount of locally produced IgA and IgG. Antigastric autoantibodies were screened in the sera and in the supernatants by means of immunohistochemistry. RESULTS: The infected patients had significantly higher concentrations of locally produced IgA, whereas the IgG concentrations were virtually the same in infected and noninfected patients. IgG or IgA antigastric autoantibodies, or both, were detectable only in the sera (38%) and supernatants (17%) of infected patients. Interestingly, the patient with the strongest local autoimmune response showed body-predominant H. pylori gastritis, with destruction of gastric glands and atrophy of the body mucosa. CONCLUSIONS: These results demonstrate that antigastric autoimmune reactions are detectable at the site of the disease and might be relevant for the pathogenesis of gastric mucosa atrophy in H. pylori gastritis.

Adult↗
PubMed2000

Rapid and specific detection of Helicobacter pylori macrolide resistance in gastric tissue by fluorescent in situ hybridisation.

BACKGROUND: The development of macrolide resistance in Helicobacter pylori is considered an essential reason for failure of antibiotic eradication therapies. The predominant mechanism of resistance to macrolides, particularly clarithromycin, is based on three defined mutations within 23S rRNA, resulting in decreased binding of the antibiotic to the bacterial ribosome. AIM: To develop an rRNA based whole cell hybridisation method to detect Helicobacter species in situ within gastric tissue, simultaneously with its clarithromycin resistance genotype. METHODS: A set of fluorescent labelled oligonucleotide probes was developed, binding either to H pylori 16S rRNA or 23S rRNA sequences containing specific point mutations responsible for clarithromycin resistance. After hybridisation and stringent washing procedures, labelling of intact single bacteria was monitored by fluorescence microscopy. The new approach was compared with PCR based assays, histology, and microbiological culture. RESULTS: In comparison with the phenotypic resistance measurement by E test, the genotypic clarithromycin resistance correlated perfectly (100%) for 35 H pylori isolates analysed. In a set of gastric biopsy specimens (27) H pylori infection was confirmed by histology (17/27) and correctly detected by whole cell hybridisation. Five clarithromycin resistant strains were identified in gastric tissue specimens directly. Furthermore, non-cultivable coccoid forms of H pylori were easily detectable by whole cell hybridisation. CONCLUSIONS: Whole cell hybridisation of rRNA holds great promise for cultivation independent, reliable, and rapid (three hours) genotypic determination of clarithromycin resistance in H pylori. Compared with PCR techniques it is independent of nucleic acid preparations, not prone to inhibition, and allows semiquantitative visualisation of the bacteria within intact tissue samples.

Anti-Bacterial Agents↗
PubMed1999

[EHBMP-2. Initial BMP analog with osteoinductive properties].

For the first time a non natural BMP-variant (EHBMP-2) with osteoinductive properties was produced by expression in E. coli through specific mutation of the amino acid sequence. The substitution of 12 N-terminal amino acids by a nonsense sequence results in a neglectible affinity of EHBMP-2 to the extracellular matrix. In vitro EHBMP-2 induces dose-dependent cartilage formation in neonatal muscle tissue. Single intramuscular implantation in mice results in the formation of an ossicle with functional active bone marrow. The size of the ossicle depends on the amount of implanted EHBMP-2 and can significantly be increased by the combination with a collagen carrier. The largest bone formation is observed after injection of EHBMP-2 containing collagen suspensions. In rats a stronger osteoinductive activity can be achieved by coupling of EHBMP-2 to collagen discs than by coupling natural BMP-2 to the same collagen carrier. Critical size defects in rats' mandibular angels can be restored by the combination of granular collagenous bone matrix (ICBM) with EHBMP-2. Further investigations have to show whether the altered pharmacokinetics of EHBMP-2 has advantages regarding its therapeutical use and tissue-engineering.

Amino Acid Substitution↗
PubMed1999

Decrease of antigastric autoantibodies in Helicobacter pylori gastritis after cure of infection.

H. pylori infection leads to the formation of autoantibodies against canalicular structures with human parietal cells in about 30% of all patients. This type of autoreactivity is associated with gastric mucosa atrophy. This study aimed to analyse the effect of cure of infection on anticanalicular autoantibodies. H. pylori infection was cured in 34 patients. Sera of these patients were screened for anticanalicular autoantibodies using an immunohistochemical method before, 10 weeks after and one year after cure of infection. Prevalence of anticanalicular autoantibodies significantly decreased from 26% before treatment to 9% after one year. The data presented in this study add new information to the possible reversibility of gastric mucosa atrophy.

Adult↗
PubMed1999

Genetic and functional characterization of the alpAB gene locus essential for the adhesion of Helicobacter pylori to human gastric tissue.

In this study, we isolated and characterized a chromosomal locus of Helicobacter pylori previously identified by transposon shuttle mutagenesis as being involved in the adhesion of the pathogen to gastric epithelial cells. Two closely homologous genes were identified, designated as alpA and alpB, encoding outer membrane (OM) proteins of 518 amino acids each. They are members of the outer membrane protein supergene family identified in the H. pylori 26695 complete genome sequence. AlpA carries a functional lipoprotein signal sequence. AlpB carries a putative standard N-terminal signal sequence and shows a strong amino-acid sequence identity to AlpA. Transposon insertion mutagenesis, immunoblotting and primer extension studies indicate that both genes are organized in an operon, but no obvious consensus promoter sequence was found upstream of the transcriptional start site. The C-terminal portion of both proteins is predicted to form a porin-like beta-barrel in the outer membrane, consisting of 14 transmembrane amphipathic beta-strands. Adhesion experiments with defined isogenic mutants indicate that both proteins are necessary for specific adherence of H. pylori to human gastric tissue. The pattern of AlpAB-dependent adherence of H. pylori to the gastric epithelial surface shows a clear difference to the BabA2-mediated adherence to Lewis, suggesting that a different receptor is involved.

Algorithms↗
PubMed1999

Helicobacter pylori induces apoptosis in gastric mucosa through an upregulation of Bax expression in humans.

BACKGROUND: Maintenance of gastric mucosal integrity depends on the balance between cell loss due to apoptosis and cell proliferation. Helicobacter pylori induces apoptosis in gastric epithelial cells, but the regulation of this process has been little studied. The Bcl-2 proteins are the best-studied family of proteins involved in the mechanism of apoptotic death. Some members of this family, such as Bcl-2, inhibit apoptosis, whereas others, such as Bax, induce it. The present study was performed to determine the apoptosis rate and mRNA and protein expression for Bax and Bcl-2 in the gastric mucosa of duodenal ulcer (DU) patients with H. pylori infection before and after H. pylori eradication. We recruited 8 H. pylori-negative control subjects and 20 DU patients (H. pylori-positive) given a 1-week triple therapy to eradicate H. pylori. The apoptosis was analyzed by means of terminal deoxyribonucleotide transferase-mediated digoxigenin-11-deoxyuridine triphosphate biotin nick-end labeling (TUNEL) staining, and the expression of mRNA for Bax and Bcl-2 by reverse transcription polymerase chain reaction (RT-PCR) and Southern blot. In all patients gastritis was assessed histologically on the basis of the Sydney classification, the presence of H. pylori, and analysis of cagA status. RESULTS: All 20 DU patients were H. pylori-positive, and 18 (90%) were CagA-positive. The apoptotic cells were infrequently identified in gastric surface epithelium by TUNEL histochemistry in H. pylori-negative controls. In DU patients infected with H. pylori, apoptotic cells were more numerous and seen deep in the gastric glands. The infection was associated with significantly upregulated expression of mRNA and protein for Bax and suppressed mRNA and protein expression for Bcl-2, as determined using RT-PCR and Western blot analysis. The Bax overexpression was significantly stronger in the antrum than in the corpus of H. pylori-infected patients. Four weeks after the eradication a marked decrease of neutrophil infiltration, an improvement of the grade of gastritis (mononuclear infiltration), and significant reduction in apoptosis rate were observed. After eradication the Bax mRNA expression was still at an increased level, whereas the Bcl-2 mRNA expression remained suppressed. CONCLUSIONS: 1) H. pylori induces apoptosis in the gastric epithelium, at least in part, due to an upregulation of proapoptotic Bax and downregulation of antiapoptotic Bcl-2, and 2) Bax mRNA and protein expression was higher in the antrum than in the corpus, and this was probably due to greater inflammatory changes observed in the antrum than in the corpus.

Adult↗
PubMed1999

[Helicobacter pylori infections and autoimmunity: the interplay in the pathogenesis of gastritis].

Recent studies suggest a significant association of Helicobacter pylori (H.p.) gastritis and antigastric autoimmunity. Sera of H.p. infected patients exhibit antigastric autoantibodies with high prevalence (over 50 percent of the cases) and with antiluminal and/or anticanalicular binding patterns on gastric mucosa. Models for the pathogenesis of this H.p. associated autoimmunity are antigenic mimicry or Th 1-induced expression of MHC class II and costimulatory molecules on gastric epithelial cells. The anticanalicular autoantibodies binding to gastric parietal cells show fine specificities for the alpha- and for the beta-subunit of the gastric H, K-ATPase, which correspond to the findings in classical autoimmune gastritis. They are significantly correlated with higher grades of corpus gastritis as well as morphologic and functional glandular atrophy of the corpus. The development of this antigastric autoimmunity apparently is a relevant pathogenic factor of the host reaction and might be crucial for the different types and outcomes of H.p. gastritis.

Autoantibodies↗
PubMed1998

Expression of the extracellular matrix signaling molecule Cyr61 is downregulated in prostate cancer.

BACKGROUND: Prostate cancer (CaP) is one of the most common neoplasms in the USA and Europe. We used differential display PCR (DD-PCR) to identify genes related to the development of prostate cancer. METHODS: The RNA of 4 patients with untreated CaP was analyzed for differentially expressed genes. Using DD-PCR, we identified a downregulated cDNA-fragment in these prostate cancer cells. This fragment (N7) was cloned and further analyzed by CMRT-PCR, Northern-blot analysis, and in situ hybridization. RESULTS: Sequence analysis revealed that N7 is identical to the 3'-untranslated region of the recently described immediate early gene Cyr61. Comparative multiplex RT-PCR with sequence specific primers showed that Cyr61 is downregulated in the tumor tissue of 7 out of 13 patients. By in situ hybridization we could demonstrate that the expression of Cyr61 is restricted to the epithelium of the prostate. Immunohistochemical analysis showed that Cyr61 protein could be found in the epithelium of normal prostatic tissue, whereas prostate cancer tissue showed a marked decrease of Cyr61 protein expression. CONCLUSIONS: Cyr61 is a member of the emerging family of extracellular signaling proteins and enhances the effect of bFGF. The changed pattern of expression Cyr61 might therefore contribute to the altered interactions between epithelial and stromal cells in prostate carcinoma.

Animals↗
PubMed1998

[Biological activity of E. coli expressed BMP-4].

BMP-4 is physiologically present in low concentrations in human bone matrix. So far the protein has only been produced in small quantities by expression in mammalian cell cultures. In this study we investigated the biological activity of E. coli-expressed BMP-4. In vitro neonatal rat muscle tissue was incubated together with BMP-4 during 4 h, followed by an incubation period of 14 days on cellulose acetate membranes in BMP-free medium. The addition of 0.4 microgram BMP-4 induced cartilage formation in 1/8 samples while 4 micrograms BMP-4 showed chondroneogenesis in 2/10 samples. When the BMP-4 concentration was increased to 40 micrograms, new cartilage formation was seen in 5/7 samples. In vivo BMP-4 was implanted intramuscularly for 3 weeks in ICR mice. Amounts of 10 micrograms rhBMP-4 and more (up to 100 micrograms) constantly induced heterotopic ossicle formation. BMP-4 was also combined with a collagen carrier and implanted for 2 and 4 weeks in the abdominal muscle of SD rats. While 0.4 microgram BMP-4 showed no bone or cartilage formation, the amount of 40 micrograms BMP-4 showed new heterotopic cartilage formation, followed by endochondral ossification in almost all samples. The results prove that E. coli-expressed BMP-4 possesses the same inductive properties as mammalian-cell-expressed BMP-4.

Animals↗
PubMed1998

Apoptosis in chronic gastritis and its correlation with antigastric autoantibodies.

In the course of time, chronic gastritis may result in gastric atrophy, as in type A gastritis, where autoimmune reactions against parietal cells result in a loss of corpus glands. Two antigastric autoantibodies have been detected in Helicobacter pylori gastritis and are described as anti-luminal and anti-canalicular autoantibodies. The aim of this study was to determine whether increased apoptosis may be responsible for the loss of gastric epithelium and whether this apoptosis is correlated with antigastric autoimmunity. Gastric biopsies from normal mucosa and Helicobacter pylori gastritis were analysed for the presence of apoptosis using the TUNEL method. Helicobacter pylori gastritis was divided into cases (1) without autoantibodies, (2) with anti-luminal, and (3) with anti-canalicular autoantibodies. Apoptotic cells of the foveolar and of the glandular epithelium in the antrum and corpus were counted. The number of apoptotic cells in the gastric mucosa was significantly increased in all cases of gastritis. The highest number of apoptotic cells was observed in the gastric glands of the corpus mucosa in Helicobacter pylori gastritis with anti-canalicular autoantibodies. Apoptosis contributes to the development of gastric atrophy and there are various types of Helicobacter pylori gastritis. The positive correlation between apoptotic cell loss in the glandular zone of the corpus mucosa and the presence of anti-canalicular autoantibodies indicates a possible link between anti-gastric autoimmunity and atrophy in this type of Helicobacter pylori gastritis--similar to that in classic type A gastritis.

Adult↗
PubMed1998

The gastric H+,K+-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy.

BACKGROUND & AIMS: A subgroup of Helicobacter pylori-infected patients develops autoantibodies to gastric parietal cell canaliculi. The aim of this study was to define the unknown autoantigen. METHODS: We screened 72 H. pylori-infected patients, 5 patients with autoimmune gastritis, and 36 healthy controls for immunoglobulin G autoantibodies to canaliculi by immunohistochemistry. The antigen specificity was determined by immunoprecipitation of the murine gastric H+,K+-adenosine triphosphatase (H+,K+-ATPase) expressed in oocytes and by immunoblotting on human gastric membranes from the body mucosa. RESULTS: Autoantibodies specific for the conformational peptides of the H+,K+-ATPase were detected in 3% (1/36) of controls, in all patients with autoimmune gastritis (5/5), in 25% (18/72) of H. pylori-infected patients, and in 47% (15/32) of the infected patients with anticanalicular autoantibodies. No other major autoantigen was identified. Atrophy in the gastric body mucosa was found in 60% (9/15) of infected patients with both anticanalicular and anti-H+,K+-ATPase antibodies, but only in 13% (5/37) of infected patients lacking both autoantibodies (P < 0.01). CONCLUSIONS: The gastric H+,K+-ATPase is a major autoantigen in H. pylori-associated antigastric autoimmunity. Thus, anti-H+,K+-ATPase autoantibodies, which are closely linked to classical autoimmune gastritis, are also significant indicators for body mucosa atrophy in chronic H. pylori gastritis.

Adult↗
PubMed1998

Inductive properties of recombinant human BMP-2 produced in a bacterial expression system.

Recombinant human BMP-2, produced in E. coli, refolded and concentrated to a purity of more than 98%, has been demonstrated to be biologically active. In vitro, amounts of 0.4 microg BMP-2 or more induced new cartilage formation in 27 out of 47 samples of a neonatal muscle tissue assay, with chondroneogenesis occurring 14 days after a four-hour contact between BMP-2 and the muscle tissue. In vivo, BMP-2 was implanted in the thigh muscle of ICR mice for a period of three weeks. Amounts of 4 microg BMP-2 and more showed heterotopic bone formation in 15 out of 17 samples. When BMP-2 was combined with a collagen carrier, amounts of 0.4 microg protein or more induced heterotopic bone formation in 30 out of 33 samples four weeks after the implantation in the abdominal wall of Sprague-Dawley rats. The results show that the E. coli-derived BMP-2 was active in different assay systems in concentrations equal to those required with mammalian cell-expressed BMP-2. It could also be demonstrated that a single morphogen (BMP-2) is enough to initiate the differentiation process associated with bone induction. The presented bacterial expression system also offers the opportunity to produce large quantities of recombinant BMP-2 for clinical applications.

Abdominal Muscles↗
PubMed1998

Epidermal growth factor and transforming growth factor alpha in duodenal ulcer and non-ulcer dyspepsia patients before and after Helicobacter pylori eradication.

BACKGROUND: Epidermal growth (EGF) and transforming growth factor alpha (TGFalpha) are potent gastric secretory inhibitors, mitogens, and mucosal protectors, but the impact of Helicobacter pylori infection on their mucosal expression and luminal release has not been clarified. METHODS: In this study, gene and immunoreactive and immunohistochemical expressions of EGF and TGFalpha were assessed in the gastric mucosa of 15 H. pylori-negative healthy normals, in 22 H. pylori-positive duodenal ulcer patients (DU) and in 24 H. pylori-positive non-ulcer dyspepsia patients (NUD). All studies in DU and NUD patients were repeated after 2 weeks of triple therapy (amoxicillin + clarithromycin + omeprazole) and 4 weeks and 2 years later. RESULTS: Immunohistochemical expression of EGF and TGFalpha in H. pylori-positive DU and NUD was significantly higher than in H. pylori-negative normals, and this increase persisted at 2 and 4 weeks after therapy but normalized 2 years later. EGF mRNA was detected in the gastric mucosa of H. pylori-positive DU before and at 2 and 4 weeks after H. pylori eradication, but it was not found 2 years after the eradication of H. pylori or in gastric mucosa of H. pylori-negative control subjects. TGFalpha mRNA was detected in the gastric mucosa independently of H. pylori status, with the stronger expression observed in the gastric mucosa of H. pylori-positive DU and NUD before eradication than after this procedure. Plasma gastrin, which was significantly increased in H. pylori-positive DU, normalized already after 2 weeks of triple therapy. The eradication rate as determined by histology after triple therapy reached 86.3% in DU patients and 90.5% in NUD patients. Two years after the eradication the H. pylori reinfection rate was 4.5% among DU patients and 4.2% among NUD. Treatment of DU patients with triple therapy resulted in complete ulcer healing. CONCLUSIONS: 1) Chronic H. pylori infection and resulting antral gastritis are associated with increased plasma gastrin and increased mucosal cell proliferation, probably due to enhanced expression of EGF and TGFalpha, and 2) the H. pylori eradication results in a decrease in plasma gastrin, but the increase in gastric TGFalpha and EGF content is sustained, suggesting that they may be involved in ulcer healing.

Adult↗
PubMed1998

Antigastric autoantibodies and gastric secretory function in Helicobacter pylori-infected patients with duodenal ulcer and non-ulcer dyspepsia.

BACKGROUND: Autoantibodies against epitopes located at the canaliculi of human parietal cells occur in about 30% of Helicobacter pylori-infected patients. This has led to the hypothesis that gastric secretory function could be inhibited by anticanalicular autoantibodies in H. pylori gastritis. METHODS: Forty-four H. pylori-infected patients with and without duodenal ulcers were screened for anticanalicular autoantibodies by means of immunohistochemistry. Plasma gastrin levels and basal and maximal gastric acid output were determined. RESULTS: Fasting gastrin levels were significantly increased in the group with anticanalicular autoantibodies. In the group of patients with non-ulcer dyspepsia the presence of anticanalicular autoantibodies was significantly correlated with an impaired basal acid secretion. CONCLUSIONS: Antigastric autoimmunity in H. pylori gastritis seems to be relevant for gastric hyposecretion either directly by inhibiting the proton pump or indirectly through the development of gastric mucosa atrophy.

Adult↗
PubMed1998

Antrum- and corpus mucosa-infiltrating CD4(+) lymphocytes in Helicobacter pylori gastritis display a Th1 phenotype.

In this study, cytokine patterns produced by CD4(+) T cells isolated from antrum or corpus gastral biopsy specimens of 10 patients with Helicobacter pylori-positive gastritis were compared. To this end, expression of intracellular cytokines (interleukin-4 [IL-4] and gamma interferon) and of CD4 was assessed by flow cytometry. Ten to 60% of the isolated CD4(+) T cells produced gamma interferon upon stimulation. With the exception of one patient, IL-4-positive CD4(+) cells were not detected. Therefore, CD4(+) cells infiltrating antrum and corpus stomach mucosa during H. pylori infection show a Th1 phenotype. This polarized Th1-type response may contribute to the inability of the immune system to eradicate H. pylori infection.

Adult↗
PubMed1998

Evidence of novel pathogenic pathways for the formation of antigastric autoantibodies in Helicobacter pylori gastritis.

Autoantibodies against gastric epithelial cells are detectable in up to 50% of patients with chronic, active Helicobacter pylori gastritis. Presence of autoantibodies against canalicular structures within human parietal cells (anticanalicular autoantibodies) correlate with gastric mucosa atrophy. It has been suggested, that molecular mimicry between H pylori and the host on the level of Lewis X and Lewis Y blood group antigens leads to these autoantibodies. This study aimed at analysing whether antigastric antibodies can be absorbed to Lewis X or Y positive H pylori strains. Sera from 14 H pylori infected patients with anticanalicular autoantibodies were effectively absorbed to H pylori. Immunohistochemical studies of the absorbed sera showed no decrease of antigastric autoreactivity. Pathogenic mechanisms other than molecular mimicry lead to the formation of antigastric autoantibodies, and epitopes other than Lewis antigens are the autoimmune targets.

Autoantibodies↗